Review
Therapeutic approach to acute crises of hepatic porphyrias
Abordaje terapéutico de las crisis agudas de porfirias hepáticas
M. Garrido Montes
, R. Pertusa Mataix, J.S. Garcia Morillo
Corresponding author
Unidad de Enfermedades Raras y Autoinmunes Sistémicas, Servicio de Medicina Interna, Hospital Universitario Virgen del Rocío, Sevilla, Spain
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Garrido Montes, R. Pertusa Mataix, J.S. Garcia Morillo" "autores" => array:3 [ 0 => array:4 [ "nombre" => "M." "apellidos" => "Garrido Montes" "email" => array:1 [ 0 => "manugartes13@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "R." "apellidos" => "Pertusa Mataix" ] 2 => array:2 [ "nombre" => "J.S." "apellidos" => "Garcia Morillo" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Unidad de Enfermedades Raras y Autoinmunes Sistémicas, Servicio de Medicina Interna, Hospital Universitario Virgen del Rocío, Sevilla, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Abordaje terapéutico de las crisis agudas de porfirias hepáticas" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1357 "Ancho" => 2917 "Tamanyo" => 192423 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Treatment according to APA severity.</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Dis: diseases, Tt: treatment, ICU: Intensive Care Unit.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Definition, symptoms, and diagnosis</span><p id="par0005" class="elsevierStylePara elsevierViewall">Porphyria is a group of genetically based inborn errors of metabolism. They are caused by abnormalities in the activity of enzymes involved in the heme synthesis pathway. Depending on the enzymatic defect and the origin of intermediate products, porphyria is classified as either hepatic or erythropoietic. There is a subgroup within hepatic porphyria characterized by the onset of what are known as acute porphyria attacks (APA). These include acute intermittent porphyria, Doss porphyria, hereditary coproporphyria, and variegate porphyria. APAs are defined as having two or more disease symptoms for more than 24 h and porphyrin levels that are greater than four to ten times the upper limit of normal. Acute porphyria can be classified as sporadic (1–3 APAs) or recurrent (more than 3 APAs) according to the frequency of these attacks over a maximum period of 12 months in the previous two years.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The manifestations of APA consist of a constellation of very heterogeneous signs and symptoms (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>), which complicates its diagnosis in the acute phase. APAs are often triggered by physiological stress: medications, menstruation, reduced calorie intake, smoking, and infections.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">A high degree of suspicion is necessary because routine additional tests do not show the telltale abnormalities of this clinical entity. Therefore, for diagnostic certainty, it is necessary to have clinical symptoms compatible with APAs and to perform specific additional tests such as the Hoesch test, which detects PBG in urine, or the determination of the precursors ALA and PBG in a 24-h urine test. It is sometimes necessary to perform plasma spectrofluorimetric screening, if available, for the diagnosis of mixed porphyria.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The purpose of this document is to systematize and standardize the therapeutic approach in the acute phase for this group of diseases.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Treatment</span><p id="par0025" class="elsevierStylePara elsevierViewall">The specific clinical management of APA treatment depends primarily on the patient’s clinical severity (<a class="elsevierStyleCrossRefs" href="#fig0010">Figs. 2–4</a>).<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">3,4</span></a> A porphyria attack is severe if it is associated with one or more of the following features: significant hyponatremia, peripheral neuropathy, urinary retention or incontinence, central nervous system involvement, and/or the onset of arrhythmias.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–6</span></a> However, any APA regardless of its severity should be halted early, even without diagnostic confirmation if there is high clinical suspicion. After stabilizing the patient, the first step in management is to identify and eliminate any triggering factors.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">5</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">In mild cases, the administration of carbohydrates (glucose saline, unless there are clinical circumstances that contraindicate it or make another perfusion solution advisable) contributes to the nutritional support of the patient and has a certain degree of a suppressive effect on ALA synthase; it was standard treatment for APA for many decades.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">6</span></a> The intravenous administration of 3,000 mL–5,000 mL of 10% glucose per day is the most common regimen. Although less effective and specific than hemin, a high carbohydrate intake may be enough to control mild acute attacks, which are characterized by the absence of neuropathy, hyponatremia, and reduced need for opioids. Fluid balance, renal function, and serum electrolytes will be monitored for as long as intravenous fluids, glucose, and electrolytes are administered.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–6</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The next step in treatment, which is the standard for moderate-severe porphyria, is hemin. It consists of intravenous hemin administration (heme arginate, Normosang® in Europe and lyophilized hematin, Panhematin® in the USA, both from Recordati, Milan, Italy) in order to replenish the HEME regulatory group in hepatocytes. The regimen is 3–5 mg/kg/day for 3–14 days, depending on the presence of clinical signs: pain and nausea usually resolve by the fourth day of treatment. On the other hand, the decrease in HEME precursor excretion becomes pronounced at 72 h.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">7</span></a> Therefore, it is recommended to monitor its use with a daily Hoesch test and if there is any rise in precursor excretion, hemin can be administered again. However, in the case of chronic excretors, monitoring with a Hoesch test loses value and thus, the need to dose hemin cycles should be clinical. It is recommended to administer it into a large caliber central vein with high blood flow via a peripherally inserted central catheter (PICC line) or another central venous catheter to reduce the risk of phlebitis arising from the formation of drug degradation products that adhere to the venous endothelium.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">8–11</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Givosiran, an interfering microRNA targeting hepatic ALA synthase 1, has recently been marketed. This drug has been shown to reduce the number of attacks in patients with recurrent acute porphyria.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">12,13</span></a> However, apart from the indication it was approved for, givosiran can be considered for off-label use for cases refractory to the aforementioned treatments according to the authors’ own experience and that of other working groups.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">8,14</span></a> For the time being, the novel drug has a good safety profile in terms of the liver and kidneys in the studies performed, although its long-term impact is still unknown. On the other hand, hyperhomocysteinemia is an effect described in series of treated patients.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">12,15</span></a> Its pathophysiology and clinical implication are still unknown, but supplementation with pyridoxine/vitamin B6 is recommended.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">16</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Kuo et al.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">17</span></a> criticize the use of ALA and PBG as risk markers for the follow-up and monitoring of both prophylactic hemin and givosiran treatment. The authors of this work propose clinical monitoring in both the acute and chronic phases of the disease.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">12</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">As a last option after these treatments, liver or liver-kidney transplantation should be considered. These therapies have had controversial results. On the one hand, they can be curative. On the other hand, patients who are transplanted become immunosuppressed for life. In addition, they have certain associated complications: hepatic artery thrombosis, renal failure, neurological decline, and iron accumulation.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">18–21</span></a> It is unclear whether APAs may be a time to consider transplantation for patients refractory to all previously proposed treatments. More scientific evidence is needed before taking a position.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">22</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Currently, molecules that target PBG deaminase are being developed in the gene therapy field; haploinsufficiency of this molecule causes AIP. On the one hand, a recombinant adenovirus targeting cytoplasmic DNA transfer is being used for PBG deaminase synthesis. The outcomes of small pilot studies in human beings have not been very satisfactory. Nevertheless, the poor response is believed to be due to insufficient transduction of the genetic material. The safety of using viral vector therapies over the long-term has not been described.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">23</span></a> On the other hand, messenger RNA is being developed for the synthesis of PBG. It has been shown to be more useful in restoring metabolic disorders more efficiently than hemin. However, it is still in the experimental study phase.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">24</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Severe APAs require monitoring patients in the intensive care unit (ICU). The following is the specific therapeutic management of complications that entail a poor prognosis in these patients:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0065" class="elsevierStylePara elsevierViewall">The main hydroelectrolytic complication is hyponatremia secondary to SIADH and the use of fluid therapy with carbohydrate supplementation. The current intravenous recommendation is to use 3% NaCl as a first measure; it is very useful in mild cases. If it is refractory, the use of urea or tolvaptan can be considered. For the latter, it is recommended to start treatment with 7.5 mg/day, as this can be effective, and titrate the dose according to response up to the usual doses of 15 mg/day, especially if it is necessary to increase free water clearance in order to safely handle large volumes of dextrose solution. The duration of tolvaptan treatment depends on the clinical situation and, to a lesser extent, the blood test results caused by the underlying disease. It is not recommended to use it for more than 30 days.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">25</span></a></p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0070" class="elsevierStylePara elsevierViewall">Porphyric neuropathy is one of the complications associated with the worst prognosis, in terms of residual axonal injury. The main trigger for this type of clinical picture is usually drugs; case series related to antiretroviral and antituberculosis drugs have been described. Its onset is usually between three and 75 days after the most common symptom: abdominal pain.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">26</span></a> Clinicians must have a high degree of suspicion and perform electrophysiological tests aimed at its diagnosis. It may mimic Guillain-Barré syndrome. The therapeutic approach is the same. However, it should be emphasized that the only measures that have been shown to improve prognosis are identification and withdrawal of the trigger, early hemin administration, monitoring in the ICU, and early rehabilitation.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">27–29</span></a></p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0075" class="elsevierStylePara elsevierViewall">It has been described that APAs can be triggers of posterior reversible encephalopathy syndrome (PRES). The pathophysiology is not well known. Several factors have been proposed: peripheral vasospasm, deficit of cofactors for the synthesis of the heme group, and the neurotoxic effects of porphyrins and their precursors.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">28–30</span></a></p></li></ul></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conclusion</span><p id="par0080" class="elsevierStylePara elsevierViewall">Managing APAs requires a comprehensive approach ranging from trigger suppression to specific treatment and long-term prevention. The administration of hemin continues to be essential for acute treatment, while the use of tolvaptan and the promising givosiran offer new treatment options.<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">15,22,31</span></a> Careful monitoring and continuous follow-up are crucial for ensuring optimal outcomes and improving the care of patients with APAs. <a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">32,33</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Funding</span><p id="par0085" class="elsevierStylePara elsevierViewall">The authors declare that they have not received funding for this study.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conflicts of interest</span><p id="par0090" class="elsevierStylePara elsevierViewall">The authors declare that they do not have any conflicts of interest.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Ethical considerations</span><p id="par0095" class="elsevierStylePara elsevierViewall">We have not used animal studies or clinical trials with human beings in this manuscript. We also did not use identifying representations that could categorize patients. Therefore, no formal written consent was required for the writing of this manuscript and its publication.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres2268629" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1891744" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2268628" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1891743" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Definition, symptoms, and diagnosis" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Treatment" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Conclusion" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Funding" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conflicts of interest" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Ethical considerations" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2024-06-22" "fechaAceptado" => "2024-07-15" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1891744" "palabras" => array:4 [ 0 => "Acute crisis porphyria" 1 => "Management" 2 => "Tolvaptan" 3 => "Givosiran" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1891743" "palabras" => array:4 [ 0 => "Crisis aguda porfiria" 1 => "Manejo" 2 => "Tolvaptán" 3 => "Givosiran" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Acute hepatic porphyria is a genetic disorder affecting enzymes involved in heme biosynthesis. The most common subtype is acute intermittent porphyria, accounting for 80% of cases. Other types include hereditary coproporphyria, variegate porphyria, and delta-aminolevulinic acid dehydratase deficiency.</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Attacks in acute hepatic porphyria are triggered by the induction of hepatic ALA synthase 1, leading to the accumulation of neurotoxic heme intermediates, delta-aminolevulinic acid, and porphobilinogen. Women experience attacks more frequently than men.</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Acute porphyria attacks are characterized by severe, diffuse abdominal pain, muscle weakness, autonomic neuropathy (including hypertension, tachycardia, nausea, vomiting, and constipation), and changes in mental status. Early recognition of the disease is crucial as it requires urgent medical attention and treatment. Management includes intravenous opioids, glucose, hemin, and the removal of triggering factors.</p><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Preventive treatment options include hormone suppression therapy, off-label prophylactic hemin, Givosiran, and exceptionally liver transplantation.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">La porfiria hepática aguda es un trastorno genético que afecta a las enzimas implicadas en la biosíntesis del hemo. El subtipo más común es la porfiria aguda intermitente (PAI), que representa el 80% de los casos. Otros tipos incluyen coproporfiria hereditaria, porfiria variegata y deficiencia de ácido delta-aminolevulínico (ALA) deshidratasa.</p><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Las crisis agudas de porfiria (CAPs) se desencadenan por la inducción de la ALA sintasa 1 hepática, lo que lleva a la acumulación de intermediarios neurotóxicos, ácido delta-aminolevulínico y porfobilinógeno (PBG). Las mujeres sufren ataques con más frecuencia que los hombres.</p><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Los ataques agudos de porfiria se caracterizan por dolor abdominal intenso y difuso, debilidad muscular, neuropatía autonómica (que incluye hipertensión, taquicardia, náuseas, vómitos y estreñimiento) y cambios en el estado mental. El reconocimiento temprano de la enfermedad es crucial ya que requiere atención y tratamiento médicos urgentes. El tratamiento incluye opioides intravenosos, glucosa, hemina y la eliminación de factores desencadenantes.</p><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Las opciones de tratamiento preventivo incluyen terapia de supresión hormonal, hemina profiláctica (indicación no autorizada), Givosiran y, excepcionalmente trasplante hepático.</p></span>" ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1746 "Ancho" => 2667 "Tamanyo" => 297902 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Most common symptoms of APA by system.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Long-term complications are shown in red.</p>" ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1640 "Ancho" => 2675 "Tamanyo" => 256116 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Management of APA according to clinical severity.</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">PSS: plasma spectrofluorimetric screening, ICU: Intensive Care Unit; HT: Hoesch test. *According to <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>.</p>" ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1357 "Ancho" => 2917 "Tamanyo" => 192423 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Treatment according to APA severity.</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Dis: diseases, Tt: treatment, ICU: Intensive Care Unit.</p>" ] ] 3 => array:8 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1493 "Ancho" => 2175 "Tamanyo" => 137624 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Treatment step according to clinical severity.</p> <p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">LT: Liver transplantation, LKT: liver-kidney transplantation.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:33 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Key terms and definitions in acute porphyrias: results of an international Delphi consensus led by the European porphyria network" "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "Members of the Acute Porphyria Expert Panel" "etal" => false "autores" => array:5 [ 0 => "P.E. 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